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Review
. 2021 Jun 16;22(12):6443.
doi: 10.3390/ijms22126443.

Pulmonary Stretch and Lung Mechanotransduction: Implications for Progression in the Fibrotic Lung

Alessandro Marchioni  1   2 , Roberto Tonelli  1   2   3 , Stefania Cerri  1   2 , Ivana Castaniere  1   2 , Dario Andrisani  1   2   3 , Filippo Gozzi  1   2   3 , Giulia Bruzzi  1   2 , Linda Manicardi  1   2 , Antonio Moretti  1   2 , Jacopo Demurtas  4 , Serena Baroncini  2 , Alessandro Andreani  2 , Gaia Francesca Cappiello  2 , Stefano Busani  5 , Riccardo Fantini  2 , Luca Tabbì  2 , Anna Valeria Samarelli  1   2 , Enrico Clini  1   2
Affiliations
Review

Pulmonary Stretch and Lung Mechanotransduction: Implications for Progression in the Fibrotic Lung

Alessandro Marchioni et al. Int J Mol Sci. .

Abstract

Lung fibrosis results from the synergic interplay between regenerative deficits of the alveolar epithelium and dysregulated mechanisms of repair in response to alveolar and vascular damage, which is followed by progressive fibroblast and myofibroblast proliferation and excessive deposition of the extracellular matrix. The increased parenchymal stiffness of fibrotic lungs significantly affects respiratory mechanics, making the lung more fragile and prone to non-physiological stress during spontaneous breathing and mechanical ventilation. Given their parenchymal inhomogeneity, fibrotic lungs may display an anisotropic response to mechanical stresses with different regional deformations (micro-strain). This behavior is not described by the standard stress-strain curve but follows the mechano-elastic models of "squishy balls", where the elastic limit can be reached due to the excessive deformation of parenchymal areas with normal elasticity that are surrounded by inelastic fibrous tissue or collapsed induration areas, which tend to protrude outside the fibrous ring. Increasing evidence has shown that non-physiological mechanical forces applied to fibrotic lungs with associated abnormal mechanotransduction could favor the progression of pulmonary fibrosis. With this review, we aim to summarize the state of the art on the relation between mechanical forces acting on the lung and biological response in pulmonary fibrosis, with a focus on the progression of damage in the fibrotic lung during spontaneous breathing and assisted ventilatory support.

Keywords: extra-cellular matrix; idiopathic pulmonary fibrosis; lung compliance; lung elastance; lung fibrosis; mechanical ventilation; spontaneous breathing; strain; stress.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Relationship between micro-strain and global stress–strain curve in human lung. The right part of the figure illustrates the stress–strain curve in the healthy lung (blue line) and in the fibrotic lung (red line). In the fibrotic lung, the stress–strain is steeper compared to healthy lung, which is due to the higher specific elastance (the slope of the curve in its linear portion); therefore, the transition from elastic to plastic behavior is achieved for lower stress–strain values. The left part of the figure illustrates the behaviors of the IPF lung during inflation, from l0, which correspond to the elastic equilibrium of the respiratory system (i.e., functional residual capacity) to 11, which corresponds to the end of tidal volume. The fibrotic lung is made up of a patchwork of areas of different elasticity predominantly in the basal and subpleural zone, in which areas of dense fibrosis and areas of spared lung tissue are contiguous. During inflation, areas of the lung with normal elasticity surrounded by inelastic tissue protrude outside the lung surface exhibiting squishy ball-like behavior. Thus, in these areas, the global lung strain does not represent the micro-strain. The traction exerted by the non-physiological cyclic micro-strain could result in epithelial injury and finally in fibrosis progression.
Figure 2
Figure 2
Mechanotransduction and intracellular pathways potentially involved in pulmonary fibrosis progression. Unphysiological mechanical stimuli act on the ECM, which in turn transmitted the physical force to integrins at the cells’ surface. Integrin clustering, through mechanosensitive focal adhesion proteins (i.e., FAK, talin, vinculin), promotes actin polymerization and cytoskeletal remodeling that can transmit forces across the nuclear envelope through specialized proteins (Nespirn, SUN, emerin), potentially influencing gene transcription. Furthermore, different intracellular pathways implicated in the induction of pulmonary fibrosis could be activated via mechanotransduction process. Rho through its effector ROCK acts as a trigger for the activity and nuclear localization of MRTF and YAP-TAZ, which in turn activated the transcriptions of profibrotic genes (COL1A1, COL1A2, CTGF, PAI-1, a SMA). Cdc-42, a GTPase protein that is part of the Rho family, is involved in alveolar regeneration after it increased mechanical tension in response to lung injury via JNK/p38 activation and nuclear YAP expression in AT2 cells. Therefore, the loss of Cdc-42 function could result in a dysfunction in alveolar renewal after lung damage. For further details, see the text.
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